Zonisamide is a new generation anticonvulsant that is typically used in combination with other antiepileptic medications for partial onset seizures. Zonisamide has not been associated with elevations in serum aminotransferase levels and clinically apparent drug induced liver disease has been reported with its use but is very rare.
Zonisamide (zoe nis' a mide) is synthetic sulfonamide derivative related somewhat in structure to acetazolamide, but not to other anticonvulsant medications. Zonisamide appears to block the spread of seizure discharges by affecting repetitive firing of voltage-sensitive sodium and calcium channels and stabilizing neuronal membranes. Zonisamide was approved for use in epilepsy in Japan in 1989 and in the United States in 2000. Current indications include adjunctive therapy for partial seizures in adults. Zonisamide is used off-label for therapy of migraine headaches, mood disturbances and recently for weight loss. Zonisamide is available as capsules of 25, 50 and 100 mg generically and under the brand name of Zonegran. The recommended initial dose in adults with epilepsy is 100 mg in one or two doses daily, with dose escalation based upon tolerance and effect to a maximum of 200 mg twice daily. Common side effects include drowsiness, dizziness, headache, nausea, poor appetite and weight loss. Rare but serious side effects include Stevens Johnson syndrome, toxic epidermal necrolysis, aplastic anemia and agranulocytosis.
Prospective studies suggest that chronic zonisamide therapy may be accompanied by mild increases in serum alkaline phosphatase levels, but it has not been linked to significant increases in serum aminotransferase levels. Clinically apparent hepatotoxicity from zonisamide is quite rare, as few case reports of hepatic injury linked to zonisamide have been published. Zonisamide is typically used in combination with other anticonvulsants and its separate role in causing liver injury is often difficult to delineate. Zonisamide has been linked to a single case report of cholestatic hepatitis associated with vanishing bile duct syndrome that ultimately resolved. More commonly, zonisamide has been linked to cases of hypersensitivity (DRESS syndrome) with rash, fever, eosinophilia, renal failure and/or mild liver test abnormalities. In most instances the hepatic injury was cholestatic and arose 3 to 8 weeks after starting therapy.
Mechanism of Injury
The mechanism of zonisamide hepatotoxicity is unknown but is likely to be hypersensitivity. Cases of drug hypersensitivity to zonisamide have been linked to HLA-A*02:07 in Japanese subjects.
Outcome and Management
A few cases of cholestatic liver injury attributed to zonisamide has been published, with complete recovery in most patients but with persistent liver test abnormalities in at least one patient. Zonisamide has not been linked to acute liver failure or chronic liver injury. Patients who develop the anticonvulsant hypersensitivity syndrome should avoid other aromatic anticonvulsants or start them only with careful monitoring. Hypersensitivity reactions to anticonvulsants including zonisamide may benefit from corticosteroid therapy but the efficacy of such therapy in altering the outcome of liver injury has not been proven.
Case 1. Cholestatic hepatitis and bile duct injury attributed to zonisamide.
[Modified from: Vuppalanchi R, Chalasani N, Saxena R. Restoration of bile ducts in drug-induced vanishing bile duct syndrome due to zonisamide. Am J Surg Pathol 2006; 30: 1619-23. PubMed Citation]
An obese 35 year old man was being treated with phentermine and topiramate for weight loss. When switched from topiramate to zonisamide, he developed fatigue, dark urine and abdominal pain followed by jaundice and itching. After 3 weeks of symptoms, laboratory testing showed significant elevations in serum bilirubin, ALT and alkaline phosphatase levels (Table). There was no rash or fever. Tests for hepatitis A, B and C and for autoantibodies were negative. Abdominal ultrasound showed echogenicity of the liver compatible with hepatic steatosis, but no evidence of biliary obstruction. Endoscopic retrograde cholangiopancreatography was normal and a liver biopsy showed cholestasis with paucity of bile ducts. He persisted in having elevations in serum enzymes and underwent repeat liver biopsies 3 and 7 months after presentation, which showed ductular proliferation and improvement in cholestasis.
||Zonisamide (dose not provided)
|Pattern:|| Mixed→Cholestatic (R=2.3, initially; later R <1.0)|
||3+ (jaundice and hospitalization)
|Recovery:||Incomplete; alkaline phosphatase still elevated one year later|
|Other medications:||Phentermine, topiramate (stopped 3 weeks earlier)|
|Time After Starting
||Time After Stopping
||Alk P (U/L)
This was a well documented example of cholestatic hepatitis presenting with histological features of bile duct injury and loss which evolved into a partially reversible bile duct vanishing syndrome. The patient had persistence of serum enzyme elevations and chronic ductular injury that was still present almost a year after onset. The injury was attributed to zonisamide, but the patient had also received topiramate that was withdrawn shortly before onset of symptoms and may have played a role in this injury. The ultimate prognosis of vanishing bile duct syndrome is variable; some patients appear to recover, others develop chronic cholestasis and cirrhosis, requiring liver transplantation.
REPRESENTATIVE TRADE NAMES
Zonisamide – Zonegran®
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NUMBER
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References updated: 06 January 2015
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Leppik IE. Zonisamide: chemistry, mechanism of action, and pharmacokinetics. Seizure 2004; 13 Suppl 1: S5-9. PubMed Citation (Review of the pharmacology and pharmacokinetics of zonisamide).
Vuppalanchi R, Chalasani N, Saxena R. Restoration of bile ducts in drug-induced vanishing bile duct syndrome due to zonisamide. Am J Surg Pathol 2006; 30: 1619-23. PubMed Citation (35 year old obese man developed fatigue and dark urine shortly after starting zonisamide and 3 weeks later had jaundice and itching [bilirubin 7.1 mg/dL, ALT 531 U/L, Alk P 531], biopsy showing bile duct loss, Alk P and ALT were still abnormal 10 months later; patient also had received topiramate 3 weeks before presentation: Case 1).
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Schwartz M, Muñana KR, Olby NJ. Possible drug-induced hepatopathy in a dog receiving zonisamide monotherapy for treatment of cryptogenic epilepsy. J Vet Med Sci 2011. [Epub ahead of print] PubMed Citation (9 year old female dog developed jaundice 3 weeks after starting zonisamide [bilirubin 4.3 mg/dL, ALT 1275 U/L, Alk P 5182 U/L], with full recovery within 4 weeks of stopping).
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Gaitatzis A, Sander JW. The long-term safety of antiepileptic drugs. CNS Drugs 2013; 27: 435-55. PubMed Citation (Review of the long term safety and adverse event profile of anticonvulsants mentions that valproate can cause fatty liver disease but that most cases of clinically apparent liver injury including acute liver failure occur within the first few months of treatment with anticonvulsants such as valproate and felbamate).
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Epilepsia 2014; 55: 1534-43. PubMed Citation
(Among 295 patients with partial seizures treated with either zonisamide or carbamazepine for 6 months, adverse events were similar with both drugs; no mention of ALT elevations or hepatotoxicity).
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